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Advances in synthesis of chiral alcohols by carbonyl bioreduction

羰基生物还原法合成手性醇的研究进展



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ChineseJournalofBioprocessEngineering
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doi:10.3969/j.issn.1672-3678.2013.03.013
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:1672-3678(2013)03-0071-12
Advancesinsynthesisofchiralalcoholsbycarbonylbioreduction
YUHuilei,HUANGLei,NIYan,XUGuochao,XUJianhe
(StateKeyLaboratoryofBioreactorEngineering,EastChinaUniversityofScienceandTechnology,Shanghai200237,China)
Abstract:Enantiopuresecondaryalcohols,askeyintermediates,playanessentialroleinpharmaceutical,
agrochemical,andchemicalindustries.Biocatalyticketonereductionisbeinggeneralyregardedasagreen
andefectiveaccesstoenantiopurealcohols,duetomildnessofreactionconditionsandfriendlinessto
environment.Anincreasingnumberofnovelandrobustenzymesbecomemoreeasilyaccessibleasaresult
oftheongoingprogressingenomics,highthroughputscreening,anddirectedevolutiontechnologies.
Advancedbioprocessengineeringprovidemoreopportunitiesforapplyingenzymetechnologiestomeet
chiralchalengesinsyntheticchemistry.
Keywords:asymmetricreduction;biocatalysis;carbonylreductases;chiralalcohols;genomemining
  
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NADH
hñ&
[43]。
-*
Šbßab Ën\1[¢“üæ¶hcd:
Vh†àÎ
(SsCR)
Q»ìä
(5%
e_ñŠ


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hñ&

6
3),
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600
g/L
h

k

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(COBE)
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22h
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̈Å
(S) 4
k

hôÀWéá
(CHBE)
(e.e.
O
>99%)[12]。
D
3 
E½¾F5G„
Fig.3 Cofactorregenerationsystemwithcosubstrate
3.2 
Š·¸G„
΀PQµ7ÂccdΌˆh^á‘.

0]ŠhÎñ&*+>‚΀Pñ&F


Qã0Îñ&.+hüý()

žŸ>Y!
.iö=ž¦nŽ’¸hFG
[44]。
àW

àW
³xÎ
(FDH)
eQb‚“|h΀PÎñ&Q
µ

d€•º:W³xÎ

ìNWQµ#C“|
3íº:W)&ˆ&×
[4546]。
õö÷³xÎ
(GDH)
_€‚Y΀Pñ&

-*Õô†à
ÎôžKõö÷³xÎôž’0–{[¢hÅ5
=

±ª[¨©ê뿒^Ž(¦·hõö÷³x
ÎhŽû

ƒjc̈

ýô

à:ôìNÅ

ÓÎN/
[47]。
¶·Yô pËJÈ
Candida
glabrata
hN†àÎ
(CgKR2)
K¶’½0ó©{[
hõö÷³xÎ
(BmGDH)
’
E.coliBL21
¢Å5=

6
4)。
:±ª¨©’^¥¦Ž(
NADP+
hŽ
û

ƒ’
7h
”
206g/L
h
OPBE
#>̈Å
(R)



ýôÀWéá
(HPBE)(e.e.
O

99%),
P2×*3=
700g/(L·d),
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Kh
27
æ
[14]。
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(directedrevolution)
OôY3ÊhLå‚{
(structureguidedconsensus)
áQp3õö÷³xÎ
(GDH)
h¦Ýå
[4849]。
ÎW³xÎ
(PTDH)
áQŒˆÃŽW^á‘Qs
ˆ“ŽW

2P
NAD(P)+
†à“
NAD(P)H[50]。
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sˆ†àÎ
,EC118991)

H2ùMNAD(P)

†à“
NAD(P)H
b
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Î
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€P½xˆÎáQýéN†à“ý
éä
(e.e.
O
>99.5%,d.e.
O
>98%)[51]。
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(PNT)
áQŒˆ
NAD(H)
O
NADP(H)
"wh÷~̈

„âYz"whu?

F+
1)。
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¶’
Pseudomonasfluorescens
h݁
PNT
K
NADP+
½ì
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NADH
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áQ‚Y
NADP+
Ù
NAD+
hñ&
[52]。
NADH+NADP+幑幐
PNT
NAD++NADPH(
F+
1)
D
4 
Š·¸F5G„
Fig.4 Enzymecouplingregenerationsystem
3}hÎñ&QµáQ-*u(ñ&äÛ

>ÌLŠ
,TTN)
Q00rsÎ“ø

#jc$
()p
TTN
=žíij]&ÌOtu
(103~
105)
hc$£X
[53]。
àd½

6ІàÎOÎ
ñ&ÎQ’2c;?[¢*–5=jõYp3†
à.h}*

Ö@˜6ׁhI&

>.*+
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e$

1)=;


©ƒŽ’^¥¦Ž(ÎP33+‡\ûh
&†à.
[5,54]。
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ºÜh†àÎ

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3+NÇå

67
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ŽLåæO=¢hëåPQζ

gMñ/Q
Šh§Š
———logP,
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ñKhnÐ
[55]。
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ñ/QŠOñWžX¶–

ñ/QŠOñWQŠ
hE€ŠO0ƒ-*Ï•

Áb-*#¼Kh
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[56],
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ï

fbc!ƒÃç#“e!ú™heür

£
M

’t íîïó÷eQ¢%‚¶’
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(ethyl6(benzyloxy)3,
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hôá

cd3b:šK‡¢we

jB3h×
*
(83.5%)
Obçh§Iüýå
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1%
éä

+‡\Å
30mol/L
P

7JÈ^§ †àýéN•“Šåýéä

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45%[58]。
0²&ŒˆhŒ
ˆåƒÑŽç

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6
5)
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Fig.5 Biocatalyticproductionofopticalyactiveethyl4chloro3hydroxybutanoatewithdiferenttailormade
catalystsintoluenebuferbiphasicsystem
  
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h
e.e.

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[60]。
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(R) 3
hôÀWéáh.
’
[BMIm][BF4]eQ¢h†à×*O×he.e.
Og’Ct÷¢h3
[61]。

AMMOENGTM101
5
ÅõráQp3
LbADH
†àù\Nh§Iüý
77 
!

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å。
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eOte“Y÷eQ

4tåWX¿e§¨©Œ
v1Ÿ h‡ãåhåæ

>•=¢’ˆ¨©&
̈¢èYÃ]j`r
[63]。
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kýéNÙ

ké¥éWéáhˆ¨©†à¢

Ot÷Qµ÷
g


[PF6]O[NTF]WX¿e5Å!Á÷Zji
3hˆŽ×*
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%‚±ª0–{[§

âNlv^§ †
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âähP2×*=ž
180g/(L·d),
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95%[65]。


WX¿e’&×*+¢
áQ>‚
25
a9&×*^rs

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e>•“ø00rs
[66]。
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‚@’c!7Â
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¡
2,2,2
1·ýéNh+æ–
‡\‘
10g/L
p3ž
50g/L[67]。
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%‚•†rh±¤

áQ‚Y WX¿e¢ñW
×

‘YWX¿eij—sh×¢Y

×Øb¶
‘IO¦Ý×ñWh›ü

9>¢™
CO2þe
b}‘IÙ¦^݁ױ¤*+¢áQìLh
sn±¤
[68]。
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、^
¶œ

¶ŠY
hèé

d“Å1¢Ï„…h&̈‚r

‚
Y&Œˆ‚A‚h>¢™þeb>¢™
CO2,ž
Å=jUÃsh¢™ˆ\O¢™Yn
[69]。
%‚¶
’
G.candidum
ä³xΌˆ^§ N†à.

’
scCO2/thY÷eQ¢áQ‚l.Í\O×*,
>"=ž)‚htu
[70]。
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>¢™
CO2h
‚g²¬±h>ª

e>•=’)&½h‚i
|}

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[71]。
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’‘
Candida
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(ã»
ìäáQu(+NÇå

Öƒ+‡\Å
70mmol/L
P
,1h
ḧ*‘
9%
u(ž
90%[72]。


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ϑ

&árÏh


áQrÏc$j`ˆ•

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^÷Ã

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éê
),
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

áQ$ùÎhƒå

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Ȓ9³^梧β NáONh^§ (x.
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[73]。
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Aspergilustereus
O
Rhizopus
oryzae
Œˆ†à£LýéNh.¢

9³5Åõ
r53æíáQp3̈*
(>99%)
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

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99%

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×
495g/L)[33]。Hildebrand
{
[75]
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ä³x遒x:
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Mxj.*
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[76]。




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ŸˆíûÐñW
*+
[77]。
£M

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2×*=ž
700g/(L·d)[78]。
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îÁäáQ=ž0Y
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g/(L·d)
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[79]。
®í5ÅüýåñWh
87
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6 
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